2/2 Brain, Behavior and Genetic Studies of the 22q11 Deletion Studies

2/2 22q11 缺失研究的大脑、行为和遗传研究

• 批准号: 7985951
• 负责人: BEVERLY S EMANUEL
• 金额: $ 96.61万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-10 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7985951
• 关键词: 22q; 22q11; 22q11 Deletion Syndrome; Accounting; Adolescence; Adolescent; Affect; Age; Alleles; Alzheimer' s Disease; Anatomy; Anxiety; Archives; Area; Attention; Authorship; Behavior; Behavioral; Behavioral Genetics; Biological; Brain; Brain Diseases; Candidate Disease Gene; Cardiac; Cardiology; Cardiovascular system; Caring; Caucasians; Caucasoid Race; Cell Line; Cells; Characteristics; Childhood; Cleft Palate; Clinical; Clinical Services; Cognitive; Collaborations; Collection; Complement; Complex; Congenital Heart Defects; Control Groups; Country; Coupled; DNA; Data; Data Collection; Databases; Detection; Development; Developmental Process; Diagnosis; Diagnostic; Diffusion Magnetic Resonance Imaging; Disease; Dissection; Down Syndrome; Early Diagnosis; Early identification; Emotions; England; Enrollment; Ensure; Epigenetic Process; Equilibrium; Evaluation; Event; Face; Family member; Fetal Development; Foundations; Frequencies; Functional Imaging; Functional Magnetic Resonance Imaging; Functional disorder; Funding; Future; Gene Expression; General Population; Genes; Genetic; Genetic Heterogeneity; Genetic Risk; Genetic Variation; Genome; Genomics; Genotype; Goals; Grant; Growth; Guidelines; Housing; Hybrids; Image Analysis; Imaging Techniques; Impairment; Incidence; Individual; Infant; Intake; International; Joints; Laboratories; Lead; Letters; Link; Magnetic Resonance Imaging; Measures; Medical; Memory; Methods; Molecular; Monitor; Morbidity - disease rate; Mutation; National Institute of Mental Health; Neurobiology; Neurocognition; Neurocognitive; Neurocognitive Deficit; Neurodevelopmental Disorder; Newborn Infant; Newsletter; Operative Surgical Procedures; Other Genetics; Pathogenesis; Pathology; Pathway interactions; Patients; Pattern; Pediatric Hospitals; Pennsylvania; Performance; Phase; Phenotype; Philadelphia; Physiological; Population; Predisposition; Preparation; Procedures; Process; Protocols documentation; Psychotic Disorders; Publications; Quality Control; Radiology Specialty; Recording of previous events; Records; Recruitment Activity; Relative (related person); Reporting; Research; Research Design; Research Personnel; Resolution; Resources; Risk; Risk Factors; Role; SNP genotyping; Sampling; Schizophrenia; Severities; Site; Specimen; Speed; Structure; Subgroup; Symptoms; Syndrome; System; Technology; Testing; Training; Universities; Update; Variant; Verbal Learning; Vision; Work; base; brain behavior; brain volume; case control; clinical phenotype; cohort; computerized; craniofacial; data management; design; disability; disturbance in affect; emerging adult; endophenotype; executive function; experience; follow-up; forging; genetic pedigree; genetic risk factor; genome wide association study; genome-wide; high risk; insertion/deletion mutation; insight; international center; meetings; morphometry; neurobehavioral; neurocognitive test; neuroimaging; neuropsychiatry; next generation; novel; public health relevance; relating to nervous system; repository; response; skills; social; structural genomics; tertiary care; tool; trait; young adult

DESCRIPTION (provided by applicant): Brain-Behavior and Genetic Studies of the 22q11DS is a collaborative RO1 between Children's Hospital of Philadelphia (CHOP) and the University of Pennsylvania (Penn). The collaboration combines genetic and neurobiologic paradigms to advance understanding of the pathogenesis of schizophrenia (SCZ). CHOP has established the largest available sample of over 800 patients with 22q11DS who have been well characterized by genetics and genomics. There is a substantial risk for developing SCZ in adolescents and young adults with 22q11DS (23-30%), with illness presentation and course similar to SCZ in the general population (1%). Penn has extensive experience in brain-behavior studies in SCZ including phenotypic characterization, computerized neurocognitive testing, and neuroimaging measures that provide complementary quantitative phenotypes. The goal of the collaboration is to capitalize on this unique sample of 22q11DS and obtain neuropsychiatric, neurocognitive, and neuroimaging phenotypes of brain structure and function. The design will include age- stratified measures of brain structure with Magnetic Resonance Imaging (MRI) using volume-based morphometry, and connectivity with Diffusion Tensor Imaging (DTI). Functional MRI (fMRI) studies will examine brain circuitry activated in response to neurobehavioral probes (Specific Aim 1). The neuropsychiatric, neurobehavioral and neuroimaging phenotypes in 22q11DS will be compared to patients with SCZ, those at clinical and genetic risk for SCZ, and cardiac and healthy controls. These groups are needed to establish the profile of phenotypic features and quantitative brain-behavior measures and their interactions (Specific Aim 2). To establish genetic mechanisms producing the neuropsychiatric, neurobehavioral and neuroimaging phenotypes, association with common SNPs will be examined using a genome-wide approach and selected candidate genes. Associations of copy number variants (CNVs) with SCZ quantitative phenotypes will be tested in 22q11DS samples both across the genome and within the 22q11DS region. Deep next generation sequencing on the "non-deleted" allele will be performed for genes in the 22q11DS region and selected candidate genes in patients with the deletion to determine whether specific mutations or alleles are associated with extreme values of SCZ-related endophenotypes in 22q11DS individuals (Specific Aim 3). Specimens will be sent to the NIMH repository for transformation and DNA extraction. Data collection and quality control will be maintained and verified data will be regularly uploaded to the NIMH repository (Specific Aim 4). The proposed project will be the first of its kind to take a common deletion associated with SCZ and elucidate its behavioral, neurobiological and genetic substrates. Beyond the potential for yielding a better understanding of a severe manifestation of 22q11DS, the results will help identify pathways leading to SCZ in the general population in a way that will point to novel treatments. PUBLIC HEALTH RELEVANCE: Schizophrenia (SCZ) is a complex brain disorder with genetic substrates. It often emerges in adolescence and early adulthood with devastating effects. Of individuals with 22q11DS, 23-30% develops the SCZ phenotype, providing a unique opportunity to probe the pathogenesis of SCZ. Integration of genomics and neurobiology is key to understanding the causes of deficits, leading to early detection and advancing novel treatments.

描述（由申请人提供）：22q11DS的脑行为和遗传研究是费城儿童医院（CHOP）和宾夕法尼亚大学（Penn）的合作RO1。该合作结合了遗传和神经生物学范式，以促进对精神分裂症发病机制的理解。CHOP已经建立了800多名22q11DS患者的最大可用样本，这些患者已经通过遗传学和基因组学进行了很好的表征。患有22q11DS的青少年和年轻成人发生SCZ的风险很大（23-30%），其疾病表现和病程与一般人群的SCZ相似（1%）。Penn在SCZ的脑行为研究方面拥有丰富的经验，包括表型表征、计算机化神经认知测试和提供互补定量表型的神经成像测量。合作的目标是利用这个独特的22q11DS样本，获得大脑结构和功能的神经精神、神经认知和神经影像学表型。该设计将包括使用基于体积的形态测量的磁共振成像（MRI）对大脑结构的年龄分层测量，以及与扩散张量成像（DTI）的连接。功能性磁共振成像（fMRI）研究将检查大脑回路对神经行为探针的反应（具体目标1）。22q11DS的神经精神、神经行为和神经影像学表型将与SCZ患者、SCZ临床和遗传风险患者以及心脏和健康对照进行比较。需要这些组来建立表型特征和定量脑行为测量及其相互作用的概况（Specific Aim 2）。为了建立产生神经精神、神经行为和神经影像学表型的遗传机制，将使用全基因组方法和选择的候选基因来检查与常见snp的关联。拷贝数变异（CNVs）与SCZ定量表型的关联将在22q11DS基因组和22q11DS区域的22q11DS样本中进行测试。将对22q11DS区域的基因和缺失患者中选定的候选基因进行“非缺失”等位基因的深度下一代测序，以确定特定突变或等位基因是否与22q11DS个体中scz相关内表型的极端值相关（specific Aim 3）。标本将被送到NIMH仓库进行转化和DNA提取。将保持数据收集和质量控制，并定期将经核实的数据上传到NIMH存储库（具体目标4）。该项目将首次采用与SCZ相关的常见缺失，并阐明其行为，神经生物学和遗传基础。除了有可能更好地理解22q11DS的严重表现外，该结果将有助于确定普通人群中导致SCZ的途径，从而指出新的治疗方法。